1. Field of the Invention
The invention relates to a method for treating both the early and late phases of allergic lung disease. In particular, the invention relates to a method for immunizing a host against allergic asthma through use of asthma-initiating antigen-encoding polynucleotide compositions.
2. History of the Prior Art
Asthma is one of the common chronic lung diseases of industrialized countries. The airway narrowing which characterizes the disease is associated with antigen stimulated immune system activation, including elevation of antigen-specific IgE levels in the early phase of the disease and eosinophil infiltration of lung tissue in the late phase of the disease.
Specifically, during the early phase of the disease, activation of Th2 lymphocytes stimulates the production of IgE antibody, which in turn triggers the release of histamine and other immune mediators from mast cells. During the late phase of the disease, IL-4 and IL-5 cytokine production by CD4+ helper T lymphocyte type 2 (Th2) cells is elevated. These cytokines are believed to play a significant role in recruiting eosinophils into lung tissue, where tissue damage and dysfunction result.
Persons suffering from allergic asthma are conventionally treated by immunization against the asthma-initiating antigen with an antigen-based composition. Antigen immunization limits the antigen-stimulated events of the early phase of allergic asthma, albeit at the risk of inducing IgE mediated anaphylaxis. However, such classical immunization schemes do not target the cytokine-mediated events of the late phase immune response in allergic asthma.
The invention consists of a method for treating allergic asthma in a host which reduces the allergic immune responses that are characteristic of both the early and late phases of the disease. This is accomplished according to the invention by administering an asthma-initiating antigen-encoding polynucleotide to the host in a manner which induces intracellular expression of the antigen in antigen presenting cells. The expressed antigen is presented to host CD4 T lymphocytes in a manner which activates class 1 helper T (Th1) lymphocytes in preference to Th2 lymphocytes.
Thus, the polynucleotide immunization scheme of the invention allows the clinician to induce tolerance to an asthma-initiating antigen in a host with little risk of stimulating the Th2 lymphocyte mediated IgE antibody production and mast cell activation events which characterize the early phase of allergic asthma. In addition, the immunization scheme of the invention also reduces Th2 cell release of IL-4 and IL-5, thus substantially limiting the eosinophil accumulation in lung tissue which characterizes the late phase of allergic asthma. In this manner, the invention provides a more efficacious, less risk-intensive means of treating allergic asthma than is presently available in the art.
In practice, a suitable candidate for treatment according to the method of the invention is a host in whom allergic asthma has been diagnosed and for whom at least one asthma-initiating antigen (i.e., a proteinaceous antigen which triggers an allergic-response in the host that results in asthmatic symptoms being experienced by the host) has been identified.
According to the method of the invention, the host is immunized with a pharmaceutical composition comprised of a recombinant expression vector (preferably a plasmid or cosmid, hereafter xe2x80x9cpolynucleotide compositionxe2x80x9d). The recombinant expression vector incorporates a polynucleotide which encodes the asthma-initiating antigen. To enhance Th1 lymphocyte activation to a therapeutically sufficient level, the polynucleotide composition is administered to a tissue of the host which contains a relatively high concentration of antigen presenting celis (e.g., skin or mucosa, such as the mucosa of the respiratory tract) as compared to other host tissues. Advantageously, targeting the dense population of antigen presenting cells present in the skin and mucosa for expression of antigen permits relatively minute doses of polynucleotide composition to be applied toward a therapeutic effect in the host.
Where desired, the recombinant expression vector of the polynucleotide composition may also code for other therapeutically significant, biologically active peptides, such as immunostimulatory cytokines (e.g., TGF-xcex2). Alternatively, such peptides or other therapeutically significant compounds may be administered in conjunction with the polynucleotide compositions of the invention.